Tertiary aminoacids

ABSTRACT

New Alpha -(acyclic tert. aminophenyl)-aliphatic acids, e.g., those of the formula   AND FUNCTIONAL DERIVATIVES THEREOF, ARE ANTI-INFLAMMATORY AGENTS.

United States Patent Carney et al.

[ 51 Sept. 19, 1972 TERTIARY AMINOACIDS Inventors: Richard William,James Carney, New Providence, NJ. 07974; George De Stevens, Summit, NJ.

07901 Assignee: Ciba-Geigy Corporation Filed: Sept. 29, 1969 Appl. No.:861,984

Related US. Application Data Continuation-impart of Ser. No. 808,331,March 18, 1969, which is a continuation-inpart of Ser. No. 792,807, Jan.21, 1969, abandoned, which is a continuation-impart of Ser. No. 757,136,Sept.3, 1968, Pat. No. 3,657,230, which is a continuation-in-part ofSer. No. 716,347, March 27, 1968, abandoned.

[56] References Cited UNITED STATES PATENTS 3,390,051 6/1968 Baker et al..260/5l8 R OTHER PUBLICATIONS Finar, l.L., Organic Chemistry, Vol. I,1963, Pub. by Richard Clay & Co. England, (CD251 F56) Page 191 Reliedon.

Primary Examiner-Lorraine A. Weinberger Assistant Examiner-L. ArnoldThaxton Attorney-Harry Goldsmith, Joseph G. Kolodny and Mario A. Monaco[57] ABSTRACT New a-(acyclic tert. aminophenyD-aliphatic acids, e.g.,those of the formula R =H or alkyl R =Il, alk(en)yl, oycloalk(on)yl orcycl0alk(en)yla yl R =alk(c n)yl, hydroxyalkyl, alkoxyalkyl or aminoalkl{ =alk(cn)yl, liydroxyalkyl, alkoxyalkyl,

alk(cn)yj, cyeloalk(on)yl-alkyl or aralkyl cycloandfunctional'derivatives thereof, are anti-inflammatory agents.

8 Claims, No Drawings TERTIARY AMINOACIDS CROSS-REFERENCES TO RELATEDAPPLICATIONS This is a continuation-in-part of application, Ser. No.808,331, filed Mar. 18, 1969, which in turn is a con tinuation-in-partof application, Ser. No. 792,807, now abandoned, filed Jan. 21, 1969,which in turn is a continuation-in-part of application, Ser. No.757,136, now US. Pat. No. 3,657,230, filed Sept. 3, 1968, which in turnis a continuation-in-part of application, Ser. No. 716,347, nowabandoned, filed Mar. 27, 1968.

SUMMARY OF THE INVENTION The present invention concerns and has for itsobject the provision of new a-( acyclic tert. aminophenyl)- aliphaticacids of the Formula I -C O OH in which R is hydrogen or lower alkyl, Ris hydrogen, lower alkyl, alkenyl, cycloalkyl, cycloalkenyl,cycloalkyl-alkyl or cycloalkenyl-alkyl, Ph is a phenylene radical, R islower alkyl, alkenyl, hydroxyalkyl, alkoxyalkyl or aminoalkyl, and R islower alkyl, alkenyl, hydroxyalkyl, alkoxyalkyl; cycloalkyl,cycloalkenyl, cycloalkyl-alkyl, cycloalkenyl-alkyl or aralkyl, whereinheteroatoms are separated from the amino nitrogen atom by at least 2carbon atoms, and R R and R together contain at least three carbonatoms, of therapeutically acceptable functional acid or aminoderivatives thereof, as well as of corresponding pharmaceuticalcompositions and of methods for the preparation and application of theseproducts. Said compositions are useful anti-inflammatory agents in thetreatment 'or management of arthritic and dermatopathologic conditions.

DESCRIPTION OF THE PREFERRED EMBODIMENT Y The lower alkyl radicals R toR represent, for example, methyl, ethyl, nor i-propyl, -butyl, -pentyl,-hexyl or -heptyl. A lower alkenyl radical R R or R is, for example,vinylyallyl, methallyl, 3-butenyl or l-pentenyl. The term lower,"referred to above and hereinafter in connection with organic radicals orcompounds respectively, defines such with up to seven, preferably up tofour, carbon atoms.

Alower alkoxy-lower alkyl radical R is, for example, 2-(methoxy, ethoxy,nor i-propoxy)-ethyl or -propyl, 3-(methoxy or ethoxy)-propyl or4-methoxybutyl. An aminoalkyl group R is, for example, (amino, monoordi-lower alkylamino, lower alkyleneimino or monoaza-, monooxa-, ormonothia-lower alkyleneimino)-lower alkyl, e.g.m-(amino, ethylamino,dimethylamino, pyrrolidino, piperidino, piperazino, 4-methylpiperazino,morpholino or thiamorpholino)-ethyl, -propyl or -butyl.

A cycloalkyl or cycloalkenyl radical R or R is preferably 3 to 7ring-membered and unsubstituted or substituted by up to 4 lower alkyls,such as cyclopropyl, 1- or 2-methyl-cyclopropyl, 1,2-, 2,2- or2,3-dimethylcyclopropyl, 1,2,2- or l,2,3-trimethylcyclopropyl or2,2,3,3-tetramethyl-cyclopropyl, cyclobutyl, 3,3- dimethyl-cyclobutyl or2,2,3-trimethyl-cyclobutyl, cyclopentyl, 2- or 3-methyl-cyclopentyl,2,5- or 3,

dimethyl-cyclopentyl, cyclohexyl, 2-, 3- or 4-methylcyclohexyl, 2,3-,2,4- or 3,5-dimethylcyclohexyl or 2,4,6-trimethyl-cyclohexyl orcycloheptyl; 2- cyclopropenyl, 2,3-dimethyl-2-cyclopropenyl, 1-, 2- or3-cyclopentenyl or -cyclohexenyl, 2- or 3-methyl-2- cyclopentenyl,3,4-dimethyl-3-cyclopentenyl or 2-, 3- or 4-methyl-l or 2-cyclohexenyl.A cycloalkyl-lower alkyl or cycloalkenyl-lower alkyl radical R or R isone of the above-mentioned lower alkyl groups, preferably such with upto four carbon atoms, having in any position thereof, preferably at theterminal carbon atom, one of said cycloalkyl or cycloalkenyl radicalsattached, e.g., cyclopropylmethyl, 2-cyclopentylethyl or3-cyclopentenylmethyl.

The phenylene radical Ph, carrying the tertiary amino group in the 2-,preferably 3- or especially 4-position, is unsubstituted or substitutedin the remaining positions by one or more than one, preferably one ortwo, of the same or different suitable substituents selected, forexample, from lower alkyl, e.g., methyl, ethyl, nor ipropyl or -bu-tyl,free etherified or esterified hydroxy or mercapto, such as lower alkoxyor lower alkylmercapto, e.g., methoxy, ethoxy, nor i-propoxy or -butoxy,methylmercapto' or ethylmercapto, halogeno, e.g., fluoro, chloro orbromo, trifluoromethyl, nitro, amino, preferably another group, such asdi-lower alkylamino, or lower alkanoylamino, e.g., dimethylamino,N-methyl-N- ethylamino, diethylamino, di-nor ipropylamino or butylamino;acetylamino or pivaloylamino, furthermore cyano, carbamoyl, di-loweralkyl-carbamoyl, carboxy, lower alkylsulfonyl, sulfo, sulfamoyl ordi-lower alkylsulfamoyl, e.g., N,N-dimethylcarbamoyl or sulfamoyl,methylor ethylsulfonyl. More particularly, the phenylene radical Phrepresents especially 1,3- or l,4-phenylene, but also (lower alkyl)-l,3-or l,4-phenylene, (lower alkoxy)-l,3- or l,4-phenylene, (halogeno)-l,3-or l,4- phenylene, (trifluoromethyl)- 1,3- or l,4-phenylene,(amino)-l,3- or l,4-phenylene or (di-lower alkylamino)-l,3- orl,4-phenylene.

, The aralkyl radical R is preferably an unsubstituted or substitutedphenyl-lower alkyl group, wherein the aromatic portion corresponds toHPh illustrated above and the lower alkyl group is preferably such withup to 4 carbon atoms. A preferred aralkyl radical is the group HPh(CHwherein n is an integer from 1 to 4.

In view of the above, the acyclic tertiary amino group represents, forexample, N-(lower alkyl, lower alkenyl,,

lower hydroxyalkyl, lower alkoxy-lower alkyl, aminolower alkyl, monoordi-lower alkylamino-lower alkyl,

lower alkyleneimino-lower alkyl or monoaza,-oxaor thia-loweralkyleneimino-lower alkyl)-N-(lower alkyl, lower alkenyl, lowerhydroxyalkyl, lower alkoxy-lower alkyl, 3 t 7-ring-membered cycloalkyl,cycloalkenyl, cycloalkyl-lower alkyl, cycloalkenyl-lower alkyl orHPh-lower alkyl)-amino, e.g., N-(methyl, ethyl, nor ipropyl, allyl,methallyl, 3-butenyl, 2-hydroxyethyl, 2- methoxyethyl, 3-aminopropyl,Z-ethylaminoethyl, 3- dimethylaminopropyl, 2-pyrrolidinoethyl, 2-piperozinoethyl or 2-morpholinoethyl)-N-(methyl, ethyl, nor ipropyl,allyl, methallyl, 3-butenyl, 2- hydroxyethyl, 2-methoxyethyl,cyclopropyl, cyclopentyl, cyclohexyl, 3-cyclopentenyl, 2-cyclo-hexenyl,cyclopropyl-methyl, 2-cyclopentylethyl, 3-cyclopentenylmethyl, benzyl,lor Z-phenethyl, tolylmethyl, anisylmethyl, chlorophenethyl,trifluoromethylbenzyl, aminophenethyl or dimethylaminobenzyl )-amino.

Functional derivatives of the acids of Formula I are preferably theiresters, for example, their lower alkyl, lower alkenyl, 3 to 7ring-membered cycloalkyl, cycloalkenyl, cycloalkyllower alkyl orcycloalkenyllower alkyl, aryl or aralkyl esters, e.g., the HPh orHPhlower alkyl esters, free or etherified hydroxy-lower alkyl, e.g.,lower alkoxyor 3 to 7 ring-membered cycloalkoxy-lower alkyl or acyclicor cyclic tert. amino-lower alkyl esters, wherein the tertiary aminogroup represents, for example, di-lower alkylamino or loweralkyleneimino, e.g., dimethylamino, diethylamino, pyrrolidino orpiperidino, or monoaza-, monooxaor monothia-lower alkyleneimino, such aspiperazino, 4-lower alkylpiperazino, e.g., 4-(methyl orethyl)-piperazino, morpholino or thiamorpholino. Other functionalderivatives of the acids of Formula I are, for example, unsubstituted orsubstituted amides or thioamides, e.g., monoor di-lower alkylamides,HPh-amides, HPh-lower alky lamides, monocyclic lower alkyleneamides,monoaza-, monooxaor monothia-lower alkyleneamides, furthermore thecorresponding thioamides, hydroxamic acids, nitriles, ammonium or metalsalts. Amino derivatives are the N-oxide, lower alkylor HPh-lower alkylquaternaries and acid addition salts.

The compounds of the invention possess valuable pharmacologicalproperties. For example, they exhibit anti-inflammatory effects, as canbe demonstrated in animal tests, using advantageously mammals, such asrats, as test objects. Such tests can be performed, for example,according to Winter et al., Proc. Soc. Exp. Bio]. and Med. lll, 544(1962). According to it, the compounds of the invention are applied, inthe form of aqueous solutions or suspensions, which may containcarboxymethylcellulose or polyethylene glycol as solubilizers, bystomach tube to male and female mature rats, in the dosage range betweenabout 0.l and 75 mg/kg/day, preferably between about 0.5 and 50mg/kg/day, advantageously between about 1 and 25 mg/kg/day. About 1 hourlater 0.06 ml of a 1 percent aqueous saline suspension of carrageenin isinjected into the rats left hind paw and 3-4 hours subsequently anyanti-inflammatory activity can be expressed by the difference of thevolume and/or weight of the edematous left paw and that of the rightpaw, as compared with said difference estimated from untreated controlanimals. According to the adjuvant arthritis t' 'est, male rats aresensitized with 0.05 ml of said I percent carrageenin suspension,applied under ether anesthesia to all four paws. After 24 hours 0.l mlof 1 percent suspension of M. butyricum is injected intradermally intothe tail and 7 days later the compounds of the invention are applied asshown above for a 14 day period. The rats are weighed once weekly andthe secondary arthritic lesions scored 3 times a week as to number andseverity. The results obtained are compared with those of untreatedarthritic rats. In view of the test results obtained, the compounds ofthe invention are useful anti-inflammatory agents in the treatment ormanagement of arthritic and dermatopathologic conditions. They are alsouseful intermediates in the preparation of other valuable products,preferably of pharmacologically active compounds.

Preferred compounds of the invention are those of Formula I in which Ris hydrogen or lower alkyl, R is hydrogen, lower alkyl, lower alkenyl or3 to 7 ringmembered cycloalkyl, cycloalkenyl, cycloalkyl-lower alkyl orcycloalkenyl-lower alkyl, Ph is unsubstituted phenylene or phenylenesubstituted by one or two members selected from the group consisting oflower alkyl, hydroxy mercapto, lower alkoxy, loweralkylmercapto,halogeno, trifluoromethyl, nitro, amino,

e.g., di-lower alkylamino, lower alkanoylamino, cyano, carbamoyl,di-lower alkyl-carbamoyl, carboxy, lower alkylsulfonyl, sulfo, sulfamoylor di-lower alkylsulfamoyl, R is lower alkyl, lower alkenyl,hydroxylower alkyl, lower alkoxy-lower alkyl, amino-lower alkyl, monoordi-lower alkylamino-lower alkyl, lower alkyleneimino-lower alkyl ormonoaza-, -oxaor -thialower alkyleneimino-lower alkyl and R is loweralkyl, lower alkenyl, hydroxy-lower alkyl, lower alkoxy-lower alkyl, 3to 7 ring-membered cycloalkyl, cycloalkenyl, cycloalkyl-lower alkyl,cycloalkenyl-lower alkyl, or HPh-lower alkyl, in which group theheteroatoms are separated from the nitrogen atom by at least two carbonatoms and R R and R together contain at least three carbon atoms, aswell as a lower alkyl ester, lower alkenyl ester, 3 to 7 ringmemberedcycloalkyl ester, cycloalkenyl ester, cycloalkyl-lower alkyl ester,cycloalkenyl-lower alkyl ester, HPh-ester, HPh-lower alkyl ester,hydroxy-lower alkyl ester, lower alkoxy-lower alkyl ester, di-loweralkylamino-lower alkyl ester, lower alkyleneimino-lower alkyl ester ormonoaza-, monooxaor monothia-lower alkyleneimino-lower alkyl esterthereof, wherein 2 hetero atoms are also separated from each other by atleast two carbon atoms, the amide, thioamide, a monoor di-loweralkylamide, monoor di-lower alkyl-thioamide, lower alkyleneamide, loweralkylene-thioamide, HPh-amide, HPh-thioamide, HPh-lower alkylamide,HPh-lower alkyl-thioamide, morpholide, thiamorpholide or hydroxamic acidthereof, the N-oxide, a lower alkyl quaternary, HPh-lower alkylquaternary or a therapeutically useful salt of these compounds.

Particularly useful are the compounds of Formula I, in which (a) R, ishydrogen or lower alkyl, R is hydrogen, lower alkyl, 3- to7-ring-membered cycloalkyl or monoor di-(lower alkyl)-cycloalkyl, Ph is1,3- or 1,4-phenylene, (lower alkyl)-l,3- or 1,4-phenylene, (loweralkoxy)-l,3- or l,4-phenylene, (halogeno)-l,3- or l,4-phenylene,(trifluoromethyl)-l,3- or l,4-phenylene or (di-low'er alkylamino)-l,3-or 1,4-phenylene, R is loweralkyl or alkenyl, hydroxy-lower alkyl orlower alkoxy-lower alkyl and R is 3 to 7 ring-membered cycloalkyl,monoor di-(lower alkyl)-cycloalkyl or HPh-lower alkyl wherein'Ph has themeaning given in this paragraph, or (b) R, is hydrogen or lower alkyl, Ris 3- to 7-ring-membered cycloalkyl or monoor di- (loweralkyl)-cycloalkyl, each of R and R is lower alkyl and Ph has the meaninggiven under item (a), or (c) R, is hydrogen or lower alkyl, each of R Rand R., is lower alkyl and Ph has the meaning given under a) of thisparagraph, a lower alkyl ester, the amide, a monoor di-lower alkylamide,the ammonium salt, an alkali metal or alkaline earth metal salt or atherapeutically useful acid addition salt of these compounds.

Preferred compounds of the invention are those of Formula ll N CHCOOH 3I R7 R5 in which a) R is hydrogen, lower alkyl or unsubstituted 3 to 6ring-membered cycloalkyl, R is hydrogen, lower alkyl, lower alkoxy,halogeno or trifluoromethyl, R is lower alkyl and R is unsubstituted 3to 6 ring-membered cycloalkyl or benzyl, or b) R is unsubstituted 3 to 6ring-membered cycloalkyl, R is hydrogen, lower alkyl, lower alkoxy,halogeno or trifluoromethyl and each of R and R is lower alkyl or eachof R R and R is lower alkyl and R is hydrogen, lower alkyl, lower alkoxyor trifluoromethyl, a lower alkyl ester, the ammonium salt, an alkalimetal salt or a therapeutically useful acid addition salt thereof.

Especially valuable are compounds of the Formula II, in which (a) R, ishydrogen, methyl, ethyl or cyclopropyl, R is hydrogen or chloro, R ismethyl or ethyl and R is cyclopentyl or cyclohexyl, or (b) R iscyclopropyl, R is hydrogen or chloro, and each of R and R is methyl orethyl or (c) each of R R, and R, is methyl or ethyl and R is hydrogen,or the methyl or ethyl ester, the ammonium salt, an alkali metal salt ora therapeutically useful acid addition salt thereof.

The compounds of this invention are prepared according to methods knownper so. For example, they are obtained by:

a. converting in a compound of the Formula Ill R4 (III) in which X, is asubstituent capable of being converted into the free or functionallyconverted CC O OH moiety R2 X, into said moiety or b. converting in acompound of the Formula lV or a functional derivative thereof, in whichX is a substituent capable of being converted into X, into said acyclictertiary amino group and, if desired, converting any resulting compoundinto another compound of the invention.

According to process (a), the compounds of the invention are preparedeither by (a) introduction of the whole free or functionally convertedacid moiety or any part thereof (preferably the carboxylic function),into compounds of Formula Ill, or by (B) liberation of said acid moietyfrom a suitable group containing already the required number of carbonatoms, i.e., the liberation of a potential carboxy or alkylidene moiety.

Accordingly, the simplest substituent X, is a hydrogen atom, a metallicgroup or a reactively esterified hydroxy group. The former is, forexample, an alkali metal, e.g., a lithium atom, or a substitutedalkaline earth metal, zinc or cadmium atom, such as halomagnesium orlower alkyl zinc or cadmium, e.g., chloro-, bromoor iodomagnesium,methyl or ethyl zinc or cadmium. A reactively esterified hydroxy groupis preferably such derived from a strong mineral or sulfonic acid, suchas a hydrohalic, sulfuric, lower alkane or benzene sulfonic acid, e.g.,hydrochloric, hydrobromic, methane-, ethane-, benzeneor ptoluenesulfonicacid. The corresponding starting material of Formula Ill is reacted withthe acid having the formula or a suitable derivative, e.g., acorresponding salt, ester, amide or nitrile thereof, in which formulasone of X, and Y, is the above-described metallic group and the othersaid reactively esterified hydroxy group, or X, is hydrogen and Y, is afree or reactively esterified hydroxy group. Such reaction is performedaccording to the classical Grignard or Friedel-Crafts syntheses, inwhich a new carbon-carbon bond is formed from separate reactants. Thelatter synthesis is performed in the presence of a Lewis acid, such asan aluminum, boron, antimony V, ferric or zinc salt, e.g., the chloridesthereof, or hydrofluoric, sulfuric or preferably polyphosphoric acid,which latter agent is advantageously used with the above glycolic acidsor their derivatives, i.e., those in which Y is hydroxy. ln case X is ahydrogen atom and Ph contains a free or functionally convertedy-carboxy-2-alkenyloxy group in the ortho or paraposition thereto, suchallyl ether starting material, e.g., that of the formulaNPliOCI-IgCI-I:CHC O R1 can be rearranged according to the Claisen(Cope) rearrangement procedure, for example, by heating it up to about300 or less, to yield compounds of Formula l in which R is lower alkenyland Ph contains a hydroxy group ortho or para to the acid moiety, orfunctional acid derivatives, e.g., esters or lactones, thereof,

The substituent X in Formula III is also the group um. Such metalcompound, ester, ether or alcoholate,

of Formula III is reacted with a reactive derivative of carbonic orformic acid, whereby both reactants at most contain one metal atom. Themetal or Grignard compound can be reacted with any suitable, metal freecarbonic or formic acid derivative, advantageously car bon dioxide ordisulfide, but also a corresponding carbonate or haloformate, e.g.,diethyl carbonate or thiocarbonate; ethyl or propyl orthocarbonate;ethyl, tert. butyl, allyl, 2-methoxyethyl, 3-chloropropyl, phenyl orbenzyl chloroformate; cyanogen or carbamoyl halides, e.g., cyanogenbromide or diethylcarbamoyl chloride. The starting material, in which Yis an ammonium or free or reactively converted hydroxy group, isadvantageously reacted with a metal cyanide, e.g., sodium or potassiumcyanide, and that in which Y 2 is free, esterifiecl or salified hydroxy,or the dehydrated unsaturated derivative thereof (wherein X is acorresponding l-alkenyl group), can also be reacted with carbonmonoxide. The latter may be applied under neutral, basic or acidicconditions respectively, eg, in the presence of sulfuric acid, underhigh pressure and/or temperature, e.g., up to 400 at. and 300,advantageously in the presence of heavy metal catalysts, e.g., nickel orcobalt salts or carbonyl derivatives thereof. The carbon monoxide mayalso be generated from appropriate sources, such as formic acid and highboiling mineral acids, e.g., sulfuric or phosphoric acid.

Another substituent X is the group wherein Y,, is a substituentconvertible into a free or functionally converted carboxy group. Theconversion of Y into the latter group can be performed either byoxidation or rearrangement. In the former case Y is, for example,methyl, hydroxymethyl, borylmethyl, hydroxyiminomethyl, formyl, lowerl-alkenyl or l-alkynyl, lower 1,2-dihydroxyalkyl or acyl, such as loweralkanoyl, alkenoyl, free or esterified carboxycarbonyl. In thecorresponding starting material of Formula lll, containing saidpotential carboxy function Y, is transformed into free or functionallyconverted carboxy according to standard oxidation methods, for example,with the use of air or pure oxygen, preferably in the presence ofcatalysts, such as silver, manganese, iron or cobalt catalysts, or withoxidation agents, e.g., hydrogen peroxide or nitric oxides, oxidizingacids or their salts, such as hypohalous, periodic, nitric orpercarboxylic acids or suitable salts thereof, e.g., sodium hypochloriteor periodate, peracetic, perbenzoic or monoperphthalic acid, heavy metalsalts or oxides, such as alkali metal chromates or permangariates;chromic or cupric salts, e.g., halides or sulfates thereof, or silver,mercuric, vanadium V, chromium Vl or manganese lV oxide, in acidic oralkaline media respectively. In said oxidations, usually the freecarboxylic acids of Formula I, or salts thereof, are obtained. However,by subjecting, for example, a hydroxyiminomethyl compound (oxime) toBeckmann rearrangement, e.g., treatment with sulfuric acid,p-toluenesulfonyl chloride or phosphorus pentachloride, or to oxidation,e.g., with hydrogen peroxide or any of said percarboxylic acids, orreacting the corresponding formyl or acyl compound (aldehyde or ketone)with hydrazoic acid according to the Schmidt reaction, e.g., in thepresence of sulfuric acid, or the aldehyde with a sulfonylornitro-hydroxamate, a nitrile, amide or hydroxamic acid will be formedrespectively. A starting material in which Y is free or esterifiedcarboxycarbonyl, e.g., lower carbalkoxy-carbonyl, can be converted intothe acid of Formula I either by oxidation, e.g., with hydrogen peroxidein acidic media, such as mineral acids, or by decarbonylation, whichpreferably is carried out by pyrolysis, advantageously in the presenceof copper or glass powder.

Finally, the substituent X, in Formula lll may be such a moiety, whichprimarily is capable of liberating the required alkylidene group Suchmoiety is, for example, the free or functionally converted group C-COO1I 0r Y5=O-CO OH Y4 wherein each of Y, or Y are convertible into R,and/or R respectively, for example, by reduction, decarboxylation,deacylation or desulfurization. For example, Y, is a free or reactivelyesterified or etherified hydroxy or mercapto group as mentioned above,e.g., hydroxy, mercapto, chloro, bromo, iodo, benzyloxy orbenzylmercapto, and Y; is a lower alkylidene, cycloalkylidene,cycloalkyl-alkylidene, 0x0 or thiono group. The

corresponding starting material, or the quaternary or p-quinonmethidesthereof, obtainable by splitting off Y H from said compounds of FormulaIII, in which at least one of R, and R is hydrogen, e.g., with the useof strong mineral acids or alkalis, can be reduced either withcatalytically activated or nascent hydrogen, such as hydrogen in thepresence of nickel, palladium or platinum catalysts, or with hydrogengenerated by electrolysis or the action of metals on acids, alk'alis oralcohols, such as zinc, amalgamated zinc, iron or tin on aqueous mineralor carboxylic acids, e.g., hydrochloric or acetic acid, zinc oraluminum-nickel alloys on aqueous alkali metal hydroxides, or sodium,potassium or their amalgams on lower alkanols. Also reducing and/ordesulfurizing agents may be applied, depending on the starting materialchosen. In case Y, is hydroxy, the reducing agent may be an aqueoussuspension of phosphorus and iodine, hydriodic acid, stannous chlorideor sodium sulfite or dithionite, or in case Y is esterified hydroxy,e.g., halogeno, an aliphatic or cycloaliphatic metal compound, e.g., acorresponding R, or R lithium or Grignard compound may be used asreducing agent. The latter metal compounds may also be applied in thereduction of said quinonmethides. In case Y, is oxo, the Clemmensen,Wolff-Kishner or l-luang-Minlon procedures may be applied, whereinnascent hydrogen or hydrazine are used, the latter advantageously in thepresence of strong alkalis, e.g., high boiling aqueous or glycolicsodium or potassium hydroxide solutions. In the reduction of mercapto,free or ketalized thiono compounds, desulfurization agents areadvantageously applied, such as mercury or copper oxide or Raney nickel.In case Y, represents carboxy, the corresponding malonic acid derivativeis decarboxylated by pyrolysis, advantageously in acidic media, or Y,stands for another acyl radical, such as lower alkanoyl or aralkanoyl,e. g., acetyl or benzoyl, the B-keto acid is subjected to acid splittingby the action of strong alkalis, e.g. those mentioned above.

Another substituent X,, also providing said alkylidene group, is anunsubstituted or substituted acetyl group, e.g.,

halogen The corresponding unsubstituted acetyl starting material isconverted into the compounds of the invention according to theWillgerodt-Kindler reaction, e.g., by the action of sulfur in thepresence of ammonia, primary or secondary amines and advantageously ofsulfonic acids, e.g., p-toluene sulfonic acid, the said substitutedacetyl compounds according to the Wolff (Arndt-Eistert) reaction, e.g.,by hydrolysis, alcoholysis, ammonolysis or aminolysis of corresponding0:- diazo-ketones, advantageously while irradiated or heated in thepresence of copper or silver catalysts, or according to the Favorskii(Wallach) reaction respectively, e.g., by the action of strong alkalisor soluble silver salts, such as silver nitrate, on correspondingahaloketones.

According to process (b), the tertiary amino group (R R )N is either 0:)introduced into the phenylene moiety Ph, or B) a primary or secondaryamino group, present therein, converted into the desired tertiary aminogroup. Accordingly, X is, for example, a hydrogen atom, a metallic groupor a free or reactively esterified hydroxy group, e.g., those groupsshown above, preferably an alkali metal or halogen atom respectively.The corresponding starting material of Formula 1V is reacted with thecompound (R R.,)N- Y,, in which one of X and Y is hydrogen or saidmetallic group, e.g., lithium or sodium, and the other said free orreactively esterified hydroxy group, e.g., fluorine or chlorine. In caseX is hydrogen and Y halogen, the reaction is carried out analogous tothe Friedel-Crafts syntheses mentioned above, i.e., in the presence ofLewis acids or, in case Y, is hydroxy, in the presence of alkalis, e.g.,potassium hydroxide. In case X is hydroxy or lower alkanoyloxy, thereaction is advantageously carried out in the presence of a dehydrationor dehydrogenation catalyst, such as a mineral acid or a salt thereof,e.g., hydrochloric acid, ammonium sulfite or sodium bisulfite, activatedaluminum oxide, Raney nickel or palladium-charcoal.

The conversion of any primary or secondary amino group X into (R ,R,,)Ncan simply be performed by transamination with the amine (R ,R.,)NH. Thelatter is advantageously used in excess and in the presence or absenceof catalysts, e.g., the above-mentioned dehydration or dehydrogenationcatalysts, and elevated temperature and/or pressure. A starting materialof Formula IV, in which X is primary or secondary amino, is furthersubstituted with the use of corresponding reactively esterifiedalcohols, such as lower alkyl, cycloalkyl or aralkyl halides, or withthe use of dehydrated, unsaturated (olefinic) derivatives thereof.

. These condensations are advantageously carried out in the presence ofacid binding agents, such as alkali metal carbonates, and the additionof the unsaturated compounds to the amino group preferably in thepresence of catalysts, e.g., copper, cobalt or molybdenum catalysts,alkali metals or their hydroxides. Said amino groups X, may also besubstituted by reductive alkylation, i.e., reaction with aliphatic oraraliphatic aldehydes or ketones in the presence of reducing agents,e.g., formic acid or its functional derivatives, or catalyticallyactivated hydrogen. Moreover, X may be a corresponding acylamino group,i.e., such in which at least one of R and R contains an oxo groupattached to the carbon atom bound to the amino-nitrogen atom. Suchacylamino group can be converted into R3I lR l by reduction,

e.g., with the use of selective reducing agents, such as boron hydride,diborane or their equivalents.

The compounds of the invention so obtained can be converted into eachother according to methods known per se. For example, resulting freeacids may be esterified with the corresponding alcohols in the presenceof a strong acid, e.g., hydrochloric, sulfuric, benzene or p-toluenesulfonic acid, or with diazo compounds, or converted into their halidesby treatment with thionyl halides or phosphorus halides or oxyhalides.Resulting esters may be hydrolyzed or transesterified in the presence ofacidic or alkaline agents, e.g., mineral or complex heavy metal acids oralkali metal carbonates or alcoholates, or treated with ammonia orcorresponding amines. Resulting acid halides may be treated withalcohols, ammonia or amines and resulting metal or ammonium salts withaliphatic or araliphatic halides or chlorosulfites, thionyl halides,phosphorus oxide, sulfide, halides or oxyhalides or other acyl halidesin order to obtain the corresponding esters, halides, anhydrides,amides, thioamides or the nitrile respectively. Resulting amides orthioamides (Willgerodt) can be hydrolyzed under acidic or alkalineconditions, e.g., with the use of aqueous mineral and/or carboxylicacids or alkali metal hydroxides, also alcoholized, transaminated ordesulfurized, e.g., with the use of mercuric oxide or alkyl halidesfollowed by hydrolysis. Resulting nitriles likewise can be hydrolyzed oralcoholyzed, e.g., with the use of concentrated aqueous or alcoholicacids or alkalis or alkaline hydrogen peroxide. A resulting ester, saltor nitrile, containing in mposition at least one hydrogen atom, can bemetallized therein, e.g., with the use of alkali metals or theirderivatives, such as phenyl lithium, triphenylmethyl sodium or sodiumhydride, amides or alcoholates, and thereupon reacted with reactiveesters of R OH and/or R OI-I. Resulting compounds may also behalogenated in the Ph-moiety, e.g., with the use of halogens, which areadvantageously applied in the presence of Lewis acids, e.g., ferric,aluminum, antimony Ill or tin IV halides, or with the use ofhalogenation agents, e.g., hydrochloric acid and hydrogen peroxide orsodium chlorate, nitrosyl chloride or bromide, bromosuccinorphthalimide. Furthermore, nitration may be applied to final products,advantageously with the use of nitric acid or nitrates under acidicconditions, e.g., in the presence of sulfuric or trifluoroacetic acidrespectively. Resulting nitro compounds may be reduced, for example,with catalytically activated or nascent hydrogen and, if desired, theprimary amino compounds obtained, either treated with reactive esters ofcorresponding alcohols or glycols, or with reactive functional acidderivatives, in order to obtain secondary, tertiary, quaternary oracylated amino compounds respectively. Said prim. amines can also betreated with nitrous acid, to yield diazonium salts, which latter can beconverted according to the Sandmeyer reaction, into the correspondinghydroxy, halogeno, cyano, alkoxy or alkylmercapto compounds, e.g., byhydrolyzing the diazonium salt at elevated temperatures, or reacting itwith cuprous halides or cyanide, or with a lower alkanol oralkylmercaptan respectively, preferably under neutral or slightly acidicor alkaline conditions. In resulting phenolic products, the hydroxy ormercapto group can be etherified, e.g., by reacting the correspondingalkali metal phenolates with lower alkyl or cycloalkyl halides orsulfonates, or resulting phenol ethers are hydrolyzed, e.g., with theuse of strong acids or acidic salts, e.g., hydrobromic and acetic acidor pyridine hydrochloride. Finally, resulting unsaturated compounds canbe hydrogenated as described above, e.g., with catalytically activatedor nascent hydrogen, in order to eliminate double bonds, e.g., in the Ror amino group and/or ester moiety.

A resulting acid can be converted into its salts according toconventional methods, for example, by reacting it with an aboutstoichiometric amount of a suitable salt-forming reagent, such asammonia, an amine or an alkali or alkaline earth metal hydroxide,carbonate or hydrogen carbonate. A salt of this type can be reconvertedinto the free acid by treatment with an acid, e.g., hydrochloric,sulfuric or acetic acid until the proper pH has been reached. Aresulting basic compound can be converted into a corresponding acidaddition salt, for example by reacting it with an inorganic or organicacid, such as a therapeutically useful acid, or with a correspondinganion exchange preparation, and isolating the desired salt. An acidaddition salt may be converted into the free compound by treatment witha base, e.g., a metal hydroxide, ammonia or a hydroxyl ion exchangepreparation. Therapeutically useful acids are, for example, inorganicacids, e.g., hydrochloric, hydrobromic, sulfuric, phosphoric, nitric, orperchloric acid, or organic acids, e.g., carboxylic or sulfonic acids,such as formic, acetic, propionic, succinic, glycollic, lactic, malic,tartaric, citric, ascorbic, maleic, hydroxymaleic, pyroacemic,phenylacetic, benzoic, 4- aminobenzoic, anthranilic, 4-hydroxybenzoic,salicylic, aminosalicylic, embonic, nicotinic, methanesulfonic,ethanesulfonic, hydroxyethanesulfonic, ethylenesulfonic,benzenesulfonic, halogenbenzenesulfonic, toluenesulfonic,naphthalenesulfonic and sulfanilic acid; methionine, tryptophan, lysineor arginine.

These or other salts, for example, the picrates, can also be used forpurification of the bases obtained; the bases are converted into salts,the salts are separated and the bases are liberated from the salts. Inview of the close relationship between the free compounds and thecompounds in the form of their salts, whenever a compound is referred toin this context, a corresponding salt is also intended, provided such ispossible or appropriate under the circumstances.

Resulting mixtures of isomers can be separated into the single isomersby methods in themselves known, e.g., by fractional distillation,crystallization and/or chromatography. Racemic products can likewise beresolved into the optical antipodes, for example by separation ofdiastereomeric salts thereof, e.g., by the fractional crystallization ofdor l-tartrates or d-a- (phenyl or l-naphthyl)-ethylamine orl-cinchonidine salts.

The above reactions are carried out according to standard methods, inthe presence or absence of diluents, preferably such as are inert to thereagents and are solvents thereof, of catalysts, condensing orneutralizing agents and/or inert atmospheres, at low temperatures, roomtemperature or elevated temperatures, at atmospheric or superatmosphericpressure.

The invention also comprises any modification of the above process,wherein a compound resulting as an intermediate at any stage thereof, isused as starting material and the remaining steps are carried out or theprocess is discontinued at any stage thereof, or in which the startingmaterial is formed under the reaction conditions or is used in the formof its salts or reactive derivatives. For example, in most of theabovedescribed oxidation methods, wherein Y is converted into a free orfunctionally converted carboxy group, the corresponding aldehydes (Y; isformyl) are formed intermediarily. According to the haloform reaction (Yis acetyl) intermediarily formed trihaloketones are hydrolyzed under theapplied alkaline conditions, to

yield the corresponding salts or esters of the acids of Formula I. Also,the quaternary or p-quinonmethides may be formed intermediarily from thecorresponding starting material in which Y is free or reactivelyesterified hydroxy, e.g., under strongly acidic or alkaline conditions,or during the reduction of compounds in which Y is oxo or thiono. Theadiazoketones are usually formed, according to Arndt- Eistert, from thecorresponding benzoic acid halides and aliphatic or cycloaliphatic (Rdiazo compounds, whereupon and above-described Wolff rearrangement isperformed. Finally, in the various reductions mentioned above,especially those of the quinonmethides, overreduction may occur, toyield products of Formula 1, or functional derivatives thereof, whereinPh is a corresponding cyclohexylene, cyclohexenylene orcyclohexadienylene radical. Such compounds, which also could be preparedfrom different sources, can be dehydrogenated either by pyrolysis in thepresence of catalysts, e.g., the above-mentioned hydrogenationcatalysts, or with the use of dehydrogenation agents, such as sulfur,selenium or derivatives thereof, e.g., dialkylsulfides or seleniumdioxide, quinones, e.g., chloranil, and the like. In the process of theinvention, those starting materials are preferably used, which lead tothose compounds of the invention, which are indicated above as thepreferred embodiments of the invention.

The starting material used is known or, if new, may be preparedaccording to the methods described for known analogs thereof. Forexample, compounds of Formula Hi can be prepared analogous to theprocess mentioned under item b), i.e. by introduction or construction ofthe tert. amino group in case X is a reactively esterified hydroxygroup, it may also be introduced either by halogenation, or nitrationfollowed by reduction, diazotization and Sandmeyer reaction. Theresulting starting material may be subsequently converted into themetallic compounds, e.g., by reaction with alkali or alkaline earthmetals, such as lithium or magnesium, or with dialkyl zinc or cadmium.The allyl ethers for the Claisen rearrangement can be prepared analogousto those described in J. Chem. Soc. 4210 (1963).

The starting material in which Y is a metallic group may be prepared asshown above, i.e., by reacting reactive esters of the correspondingbenzylalcohols with alkali or alkaline earth metals or dialkyl zinc orcadmium. Otherwise, according to Friedel-Crafts, easily obtainablelinear or cyclic alkanoor alkenophenones N-rnoom may be reduced eitherwith lithium aluminum hydride or with R -magnesium halides, or

NPh-

a Grignard compounds reacted with R,COR to yield the correspondingbenzyl alcohols, whose hydroxy group may be reactively esterified orsalified according to well-known methods, e.g., by reaction withphosphorus, thionyl or sulfonyl halides, alkali or alkaline earth metalsrespectively and the resulting esters or salts may be converted intoethers either by reaction with alcoholates or reactive estersrespectively. The compounds in which Y2 is an ammonium group, can beobtained from the former reactive esters and secondary amines and theresulting tertiary amines are quaternized in the usual manner, e.g., byreaction with lower alkyl or aralkyl halides.

The starting material containing Y can be obtained from the formercompounds in which Y is a metallic group, by reacting them with a methylhalide, formaldehyde, a formyl halide, lower alkanal, alkenal orhydroxyalkanal or a lower alkanoyl, alkcnoyl or oxalyl haliderespectively and, if desired, dehydrating resulting alcohols by theaction of acidic agents, e. g., sulfuric acid or phosphorus pentoxide,to yield unsaturated derivatives thereof. The latter, e.g., methylidenecompounds, may be reacted with boranes in order to obtain borylmethylcompounds and aldehydes with hydroxylamine, to yield thehydroxyiminomethyl compounds (oximes). The aldehydes, i.e., compounds inwhich Y is formyl, can also be obtained from said ketones be reactionwith dimethylsulfoniummethylide or dimethyloxysulfoniummethylide(generated from the corresponding trimethylsulfonium salts) andrearranging the resulting ethyleneoxides to the corresponding aldehydesby the action of Lewis acids, e.g., p-toluene sulfonic acid or boron.trifluoride or according to the Darzens condensation by reacting theabove ketones with a-halo-alkanoic or alkenoic acid esters in thepresence of alcoholates, e.g., potassium tert. butoxide, saponifying theglycidic esters formed and rearranging and decarboxylating them,advantageously in acidic media, e.g., sulfuric acid.

The starting material containing Y.,, which represents free, esterifiedor etherified hydroxy or mercapto, can be prepared according to thecyanohydrin or analog syntheses, e. g., by reaction of compounds ortheir thiono analogs, with aqueous potassium cyanide under acidicconditions and, if desired, converting resulting nitriles into otheracid derivatives and/or alcohols into corresponding mercapto compoundsor reactive esters or ethers thereof, or dehydrating them to unsaturatedderivatives. The compounds in which Y 5 is oxo or thiono can be obtainedaccording to Friedel- Crafts with the use of suitable compounds andoxalyl halides. The resulting phenylglyoxylic acid esters may then bereduced with R Grignard compounds, if desired, followed by dehydration.Said compounds may also be prepared according to the Ando synthesis byreaction with mesoxalates in the presence of stannic chloride. Theresulting adduct can either be hydrogenated, the malonate formedmetallized and reacted with a reactive ester of Rz-OH or saponified anddecarboxylated.

Finally the a-diazoketones are obtained from corresponding benzoic acidhalides and R -diazo compounds and the a-haloketones by halogenating ofthe corresponding alkanophenones or reacting the former a-diazoketoneswith hydrohalic acids. The starting material of Formula 1V is preparedanalogous to the process mentioned under item (a), by selecting startingmaterials containing X or a group capable of being converted into Xadvantageously nitro, instead of The pharmacologically active compoundsof the invention are useful in the manufacture of pharmaceuticalcompositions containing an effective amount thereof in conjunction oradmixture with excipients suitable for either enteral, parenteral ortopical application. Preferred are tablets and gelatin capsulescomprising the active ingredient together with (a) diluents, e.g.,lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/orglycine, (b) lubricants, e.g., silica, talcum, stearic acid, itsmagnesium or calcium salt and/or polyethyleneglycol, for tablets also(c) binders, e.g., magnesium aluminum silicate, starch paste, gelatin,tragacanth, methylcellulose, sodium carboxymethylcellulose and/orpolyvinylpyrrolidone, if desired, (d) disintegrants, e.g., starches,agar, alginic acid or its sodium salt, enzymes of the binders oreffervescent mixtures and/or (e) adsorbents, colorants, flavors andsweeteners. Injectable compositions are preferably aqueous isotonicsolutions or suspensions, and suppositories or ointments areadvantageously fatty emulsions or suspensions. They may be sterilizedand/or contain adjuvants, such as preserving, stabilizing, wetting oremulsifying agents, solution promoters, salts for regulating the osmoticpressure and/or buffers. Said pharmaceutical compositions may alsocontain other therapeutically valuable substances. They are preparedaccording to conventional mixing, granulating or coatingmethodsrespectively and contain about 0.1 to 75 percent, preferablyabout 1 to 50 percent of the active ingredient.

The following examples are intended to illustrate the invention and arenot to be construed as being limitations thereon. Temperatures are givenin degrees Centigrade, and all parts wherever given are parts by weight.

EXAMPLE 1 10 g ethyl 4-dimethylaminophenyl-acetate hydrochloride aredissolved in the minimum amount of water and the solution made basicwith 5N aqueous sodium hydroxide. The mixture is extracted with diethylether, the extract dried, filtered and the filtrate added dropwise tothe gray mixture of 500 ml liquid ammonia, 1.26 g sodium and 1 crystalferric nitrate nonahydrate while stirring, and stirring is continued for1 hour. Hereupon, 6.9 g methyl iodide are addeddropwise and stirring iscontinued for 2 hours. 'After the addition of 7 g ammonium chloride, theammonia is allowed to evaporate, the residue is taken up in 25 percentaqueous sodium hydroxide and the mixture refluxed for 24 hours. It isneutralized with 3N hydrochloric acid to a pH of about 4.5 and themixture extracted with diethyl ether. The extract is dried, filtered,evaporated and the residue recrystallized from diethyl ether-petroleumether, to yield the a-(4- dimethylaminophenyl)-propionic acid of theformula melting at l28-130.

The starting material is prepared as follows: The mixture' of 50 g4-dimethylamino-acetophenone, 150 ml morphol'ine, 9 g sulfur and 2 gp-toluene sulfonic acid is refluxed for 15 hours. It is evaporated invacuo and the residue recrystallized from acetone to yield the (4-dimethylaminophenyl)-thioacetmorpholid, melting at 138l40.'

21 g thereof are dissolved in 200 ml concentrated hydrochloric acid andthe mixture refluxed for 2 hours. It is evaporated in vacuo, the residuetaken up in ml saturated ethanolic hydrochloric acid and the mixturerefluxed for 15 hours. It is evaporated invacuo, the residue taken up inwater, the solution washed with diethyl ether and the aqueous layer madebasic with aqueous sodium hydroxide. It is extracted with diethyl ether,the extract dried, filtered, and the filtrate gassed with hydrogenchloride. The precipitate formed is filtered off to yield the ethyl4-dimethylaminophenylacetate hydrochloride melting at l32- 1 34.

EXAMPLE 2 The mixture of 3.8 g a(4-nitrophenyl)-propionic acid, 100 mlpercent aqueous ethanol, 75 ml 40 percent aqueous formaldehyde and l g10 percent palladium on charcoal is hydrogenated under normal conditionsand, after about 2 hours, the theoretical amount of hydrogen has beenabsorbed. It is filtered, the filtrate evaporated in vacuo, the residuetaken up in N aqueous sodium hydroxide and the solution acidified with Nhydrochloric acid to a pH of 4.0-4.5. The mixture is extracted 3 timeswith 200 ml chloroform each, the combined extracts dried, filtered,evaporated and the residue recrystallized from methylenechloride-diethyl ether, to yield the a-(4-dirnethylaminophenyl)-propionic acid melting at l28130; it is identical with the productobtained according to Example 1.

EXAMPLE 3 To 67 ml N boronhydride in tetrahydrofuran, kept undernitrogen, the solution of 10 g ethyl a-(4-acetyl-N-methylaminophenyl)-propionate in 60 ml tetrahydrofuran is addeddropwise during 1 hour while stirring and cooling in an ice bath. Themixture is slowly heated and refluxed for 1 hour. After cooling, 50 mlsaturated ethanolic hydrogen chloride are added and refluxing iscontinued for 1 hour. The mixture is evaporated in vacuo, the residuetaken up in 50 ml saturated ethanolic hydrogen chloride and againrefluxed for 1 hour and evaporated in vacuo. The residue is taken up in50 ml water and the mixture extracted with diethyl ether and methylenechloride. The combined extract is dried, filtered, evaporated, theresidue distilled and the fraction boiling at 148 collected, to yieldthe ethyl a-(4-N-ethyl-N- methylaminophenyl)-propionate of the formulaThe starting material is prepared as follows: Through the stirred,refluxing mixture of 5 liters anhydrous ethanol and 1 kg4-aminophenyl-acetic acid, dry hydrogen chloride is bubbled for 5.5hours and stirring and refluxing is continued for 4 hours, and aftercooling overnight to the mixture is filtered and the residue washed withcold anhydrous ethanol. It is dissolved in 8 liters water and 50 mlportions of 50 percent aqueous sodium hydroxide are added while stirringuntil the mixture is basic and stirring is continued for 1 hour at roomtemperature. The precipitate formed is filtered off and washed withwater, to yield the ethyl 4- aminophenyl-acetate, melting at 47-49.

200 g thereof are dissolved in 250 ml acetic acid anhydride and thesolution allowed to stand for 10 minutes. It is poured onto [.5 litersof ice and water while stirring, the precipitate formed filtered off andwashed with water, to yield the ethyl 4- acetylaminophenyl-acetatemelting at 75-78.

The solution of 170 g thereof in ml diethyl ether is added to themixture, prepared from 20.38 g sodium, 2 liters anhydrous ammonia and afew crystals of ferric nitrate nonahydrate, during 25 minutes whilestirring. Thereupon the solution of 120.28 g methyl iodide in 50 mldiethyl ether is added dropwise over 20 minutes and stirring iscontinued for 1 hour Thereupon 50g ammonium chloride are added, themixture evaporated and the residue taken up in diethyl ether and dilutedaqueous sodium hydroxide. The basic solution is ex- 7 EXAMPLE 4Preparation of 10,000 tablets each containing 50.0 mg of the activeingredient:

Formula: a-(4-dimethylaminophenyl)- propionic acid 500.00 g Lactosel,706.00 g Corn starch 90.00 g Polyethylene glycol 6,000 90.00 g Talcumpowder 90.00 3 Magnesium stearate 24.00 g Purified water p.s.

PROCEDURE All the powders are passed through a screen with openings of0.6 mm. Then the drug substance, lactose, talcum, magnesium stearate andhalf of the starch are mixed in a suitable mixer. The other half of thestarch is suspended in 45 ml water and the suspension added to theboiling solution of the polyethylene glycol in 180 ml water. The pasteformed is added to the powders which are granulated, if necessary, withan additional amount of water. The granulate is dried overnight at 35,broken on a screen with 1.2 mm openings and compressed into tabletsusing concave punches with 7.1 mm diameter, uppers bisected.

EXAMPLE 5 Preparation of 10,000 tablets each containing 10.0 mg of theactive ingredient:

Formula: ethyl a-(4-N-cthyl-N-mcthylaminophcnyl)-propionatc g Lactosel,l 57.00 g Corn starch 75.00 g Polyethylene glycol 6,000 75.00 g Talcumpowder 75.00 g Magnesium stearate 18.00 g Purified water q.s.

PROCEDURE All the powders are passed through a screen with openings of0.6 mm. Then the drug substance, lactose, talcum, magnesium stearate andhalf of the starch are mixed in a suitable mixer. The other half of thestarch is suspended in 40 ml water and the suspension added to theboiling solution of the polyethylene glycol in ml water. The pasteformed is added to the powders which are granulated, if necessary, withan additional amount of water. The granulate is dried overnight at 35,broken on screen with 1.2 mm openings and compressed into tablets usingconcave punches with 6.4 mm diameter, uppers bisected.

EXAMPLE 6 According to the methods described in the previous examples,the following compounds are prepared from equivalent amounts ofcorresponding starting materials:

l a-(4-dimethylaminophenyl)-3-butenoic acid 2) a-cyclopropyl-a-(4-diethylaminophenyl )-acetic acid 3)B-cyclopropyl-a-(4-di-n-butylaminophenyl EXAMPLE 7 The mixture of gethyl a-(4-N-ethyl-N- methylaminophenyl)-propionate and 100 ml 50percent aqueous sodium hydroxide is refluxed for 6 hours, cooled andwashed with diethyl ether. It is acidified with hydrochloric acid to apH or 5.5 and extracted with diethyl ether. The extract is dried,evaporated and the residue recrystallized from hexane, to yield the a-(4-N-ethyl-N-methylaminophenyl)-propionic acid of the formula NOHCOOH lC2115 CH1 melting at 65-67.

EXAMPLE 8 The mixture of 10.9 g ethyl 4-aminophenyl-acetate, 10 g sodiumcarbonate, g n-butyl iodide and 200 ml dimethylformamide is refluxed for12 hours and evaporated in vacuo. The residue is taken up in water, themixture extracted with diethyl ether, the extract dried, filtered andevaporated The residue is distilled and the fraction boiling at l22l24l0.28 mmHg collected, to yield the ethyl4-di-n-butylamino-phenylacetate of the formula We claim: 1. The a-(tert.aminophenyl)-aliphatic acid of the formula in which R is hydrogen orlower alkyl, R is hydrogen, lower alkyl, lower alkenyl, 3-to7-ring-membered cycloalkyl, cycloalkenyl, cycloalkyl-lower alkyl orcycloalkenyl-lower alkyl, Ph is 1,4-phenylene, (loweralkyl)-l,4-phenylene, (lower alkoxy)-l,4-phenylene, (chloro)-l,4-phenylene, (trifluoromethyl)-l ,4phenylene or (di-loweralkylamino)-l,4-phenylene, R is lower alkyl, lower alkenyl,hydroxy-lower alkyl, lower alkoxy-lower alkyl or amino-lower alkyl, andR is lower alkyl, lower alkenyl, hydroxy-lower alkyl, lower alkoxy-loweralkyl, 3- to 7-ring-membered cycloalkyl, cycloalkenyl, cycloalkyl-loweralkyl, cycloalkenyllower alkyl or H-Ph-lower alkyl, in which amino groupI m N n the hydroxy, alkoxy or amino groups present in R or R areseparated from the nitrogen atom by at least two carbon atoms, and R Rand R together contain at least three carbon atoms, or a lower alkylester or a therapeutically usefulsalt thereof.

2. A compound as claimed in claim 1, in which Formula R is hydrogen orlower alkyl, each of R R and R is lower alkyl and Ph is l,4-phenylene',(lower alkoxy )-l ,4-phenylene, (chloro)-l ,4-phenylene,(trifluoromethyl)- 1,4-phenylene or (di-lower alkylamino)-l,4-phenylene,a lower alkyl ester, the ammonium salt, an alkali metal or alkalineearth metal salt or a therapeutically useful acid addition salt of thesecompounds.

3. A compound as claimed in claim 1 and having the formula in which R ishydrogen, lower alkyl or unsubstituted 3 to 6 ring-membered cycloalkyl,R is hydrogen, lower alkyl, lower alkoxy, chloro or trifluoromethyl, Ris lower alkyl and R is unsubstituted 3 to 6 ring-membered cycloalkyl orbenzyl, a lower alkyl ester, the ammonium salt, an alkali metal salt ora therapeutically useful acid addition salt thereof.

4. A compound of the formula shown in claim 3, in A which R isunsubstituted 3 to 6 ring-membered cycloalkyl, R is hydrogen, loweralkyl, lower alkoxy, chloro or trifluoromethyl and .each of R and R8 islower alkyl, a lower alkyl ester, the ammonium salt, an alkali metalsalt or a therapeutically useful acid addition salt thereof.

5. A compound of the formula shown in claim 3, in which each of R R andR is lower alkyl and R is hydrogen, lower alkyl, lower alkoxy ortrifluoromethyl, a lower alkyl ester, the ammonium salt, an alkali metalsalt or a therapeutically useful acid addition salt thereof.

6. A compound as claimed in claim 3, wherein R is hydrogen, methyl,ethyl or cyclopropyl, R is hydrogen or chloro, R is methyl or ethyl andR is cyclopentyl or cyclohexyl or the methyl or ethyl ester, theammonium salt, an alkali metal salt or a therapeutically useful acidaddition salt thereof.

7. A compound as claimed in claim 4, wherein R is cyclopropyl, R ishydrogen or chloro, and each of R and R is methyl or ethyl or the methylor ethyl ester, the ammonium salt, an alkali metal salt or atherapeutically useful acid addition salt thereof.

8. A compound as claimed in claim 5, wherein each of R R and R is methylor ethyl and R, is hydrogen, or the methyl or ethyl ester, the ammoniumsalt, an alkali metal salt or a therapeutically useful acid additionsalt thereof.

2. A compound as claimed in claim 1, in which Formula R1 is hydrogen orlower alkyl, each of R2, R3 and R4 is lower alkyl and Ph is1,4-phenylene, (lower alkoxy)-1,4-phenylene, (chloro)-1,4-phenylene,(trifluoromethyl)- 1,4-phenylene or (di-lower alkylamino)-1,4-phenylene,a lower alkyl ester, the ammonium salt, an alkali metal or alkalineearth metal salt or a therapeutically useful acid addition salt of thesecompounds.
 3. A compound as claimed in claim 1 and having the formula inwhich R5 is hydrogen, lower alkyl or unsubstituted 3 to 6 ring-memberedcycloalkyl, R6 is hydrogen, lower alkyl, lower alkoxy, chloro ortrifluoromethyl, R7 is lower alkyl and R8 is unsubstituted 3 to 6ring-membered cycloalkyl or benzyl, a lower alkyl ester, the ammoniumsalt, an alkali metal salt or a therapeutically useful acid additionsalt thereof.
 4. A compound of the formula shown in claim 3, in which R5is unsubstituted 3 to 6 ring-membered cycloalkyl, R6 is hydrogen, loweralkyl, lower alkoxy, chloro or trifluoromethyl and each of R7 and R8 islower alkyl, a lower alkyl ester, the ammonium salt, an alkali metalsalt or a therapeutically useful acid addition salt thereof.
 5. Acompound of the formula shown in claim 3, in which each of R5, R7 and R8is lower alkyl and R6 is hydrogen, lower alkyl, lower alkoxy ortrifluoromethyl, a lower alkyl ester, the ammonium salt, an alkali metalsalt or a therapeutically useful acid addition salt thereof.
 6. Acompound as claimed in claim 3, wherein R5 is hydrogen, methyl, ethyl orcyclopropyl, R6 is hydrogen or chloro, R7 is methyl or ethyl and R8 iscyclopentyl or cyclohexyl or the methyl or ethyl ester, the ammoniumsalt, an alkali metal salt or a therapeutically useful acid additionsalt thereof.
 7. A compound as claimed in claim 4, wherein R5 iscyclopropyl, R6 is hydrogen or chloro, and each of R7 and R8 is methylor ethyl or the methyl or ethyl ester, the ammonium salt, an alkalimetal salt or a therapeutically useful acid addition salt thereof.
 8. Acompound as claimed in claim 5, wherein each of R5, R7 and R8 is methylor ethyl and R6 is hydrogen, or the methyl or ethyl ester, the ammoniumsalt, an alkali metal salt or a therapeutically useful acid additionsalt thereof.